Absence of a HIV-1 animal model of AIDS has been a hindrance to vaccine and therapeutic strategies. The overall goal of this proposal is to further characterize and define new innate barriers to lentiviral replication in order to develop a macaque model of HIV-1 infection and disease using pig-tailed macaques (PTM, M. nemestrina). In contrast to other Old World Monkey species, the PTM is uniquely susceptible to HIV-1, although the virus is rapidly cleared. Our past studies indicate that the susceptibility of PTMs to HIV-1 is in part due to the absence of TRIM5? expression or a post-entry block mediated by other novel TRIM5 isoforms. Furthermore, we have found that an HIV-1 clone containing a minimal SIVmne vif gene (PTM-tropic HIV-1) replicates and persists in the PTM host for at least 4 years and is capable of causing CD4+ T-cell loss. While the level of replication is low, the data provide evidence that incorporation of the SIV vif is required for persistent HIV-1 infection of PTMs. What remains unclear is how viral replication is controlled in the host and the viral adaptations necessary for escape and robust replication. Our recent data indicate that PTM-tropic HIV-1 is potently inhibited by IFN?. Interestingly, we have identified variant viruses that confer partial resistance to IFN? -induced restriction, indicating that PTM tropic HIV-1 may evolve to counteract effectors of the IFN response. In this application, we propose to test a hypothesis that viral determinants that overcome IFN-inducible inhibitors will persistently infect and robustly replicate in the PTM host. We will address the hypothesis through specific aims that identify and characterize a novel IFN ? -inducible factor targeted by the viral resistance determinant, and examine the replication fitness and pathogenicity of IFN? -resistant PTM- tropic HIV-1 clones. These studies will provide important insight into the interaction between HIV and the innate immune response and are expected to result in a macaque model of HIV-1 infection for drug and vaccine development and cure strategies.